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WO2014050105A1 - Acétate d'ulipristal amorphe - Google Patents

Acétate d'ulipristal amorphe Download PDF

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Publication number
WO2014050105A1
WO2014050105A1 PCT/JP2013/005708 JP2013005708W WO2014050105A1 WO 2014050105 A1 WO2014050105 A1 WO 2014050105A1 JP 2013005708 W JP2013005708 W JP 2013005708W WO 2014050105 A1 WO2014050105 A1 WO 2014050105A1
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WIPO (PCT)
Prior art keywords
ulipristal acetate
amorphous
ulipristal
crystalline
acetate
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PCT/JP2013/005708
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English (en)
Inventor
Shigeki Iwashita
Hiroyuki Hayashi
Koichi Miyazaki
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Aska Pharmaceutical Co Ltd
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Aska Pharmaceutical Co Ltd
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Priority to JP2015515332A priority Critical patent/JP6200493B2/ja
Publication of WO2014050105A1 publication Critical patent/WO2014050105A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
    • C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens

Definitions

  • the present invention relates to a novel ulipristal acetate (in particular, an amorphous ulipristal acetate) useful as a contraception or as an agent for preventing and/or treating uterine leiomyoma or other agents, and relates to a process for producing the ulipristal acetate.
  • a novel ulipristal acetate in particular, an amorphous ulipristal acetate
  • UPA Ulipristal acetate [17alpha-acetoxy-11beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione; hereinafter, may be referred to as UPA], which is a steroid compound possessing antiprogestational activity and antiglucocorticoidal activity, is on the market as an emergency contraceptive drug in the United States and Europe.
  • Japan Patent No. 2953725 publication JP-2953725B, PTL 1 discloses a crystalline UPA having a melting point at a temperature of 118 to 121 o C obtained by recrystallization from a mixed solvent of methanol and water.
  • WO96/30390 publication discloses a crystalline UPA having a melting point at a temperature of 183 to 185 o C obtained by crystallization from diethyl ether.
  • 2006-519255 JP-2006-519255A, PTL 3 discloses a crystalline UPA having a melting point at a temperature of 183 to 185 o C obtained by recrystallization from an ethanol aqueous solution (90%).
  • Japanese Patent Application Laid-Open Publication No. 2006-515869 JP-2006-515869A, PTL 4 discloses a crystalline UPA having a melting point of 189 o C obtained by recrystallization from an ethanol/water (80/20) mixed solvent.
  • JP-2009-539964A, PTL 5 discloses a crystalline UPA having a melting point at a temperature of 184 to 186 o C obtained by recrystallization from a mixed solvent of ethanol (230 mL) and water (260 mL).
  • novel ulipristal acetate in amorphous form useful as an agent for preventing and/or treating uterine leiomyoma or other agents, and to provide a process for producing the ulipristal acetate.
  • the novel ulipristal acetate may be useful as a contraceptive, e.g., an emergency contraceptive.
  • the novel ulipristal acetate in amorphous form may be also useful as a drug, for instance for treating and/or preventing a gynecological disorder such as uterine fibroids or leiomyoma, endometriosis, uterine bleedings, pain associated with dislocation of endometrium and the like.
  • an amorphous ulipristal acetate which is different from a conventional crystalline form, can be obtained without coexistence with other forms by dissolving an ulipristal acetate in a specified solvent and condensing (solidifying or drying) the solution, and that an ulipristal acetate substance containing the amorphous ulipristal acetate has excellent characteristics (such as solubility and absorption) and can improve bioavailability.
  • An amorphous form of ulipristal acetate of the invention may enable to decrease the dosage of ulipristal acetate to administer to the patient so as to obtain the requested therapeutic or contraceptive effect.
  • the present invention was accomplished based on the above findings.
  • a first aspect of the present invention is an amorphous (amorphous-form or noncrystalline) ulipristal acetate.
  • said amorphous ulipristal acetate has an X-ray diffraction pattern as depicted in Fig. 1.
  • the X-ray diffraction pattern is obtained with a diffractometer equipped with a Cu K alpha-1 radiation source.
  • the amorphous ulipristal acetate of the invention has a differential scanning calorimetry spectrum, which exhibits an exothermic peak of about 135 to 145 o C.
  • the amorphous ulipristal acetate of the invention may further have differential scanning calorimetry spectrum as depicted in Fig. 2.
  • Another aspect of the invention is an ulipristal acetate substance (also called herein ⁇ ulipristal acetate mixture ⁇ ) comprising the amorphous ulipristal acetate.
  • the ulipristal acetate substance may further contain a crystalline ulipristal acetate (polymorphic crystal of ulipristal acetate).
  • the crystalline ulipristal acetate may be selected among, for example, (1) a crystalline polymorphic form A (crystal A) of an ulipristal acetate having an X-ray powder diffraction pattern comprising diffraction peaks at the following diffraction 2theta angles: (2) a crystalline polymorphic form B (crystal B) of an ulipristal acetate having an X-ray powder diffraction pattern comprising diffraction peaks at the following diffraction 2theta angles: and (3) a crystalline polymorphic form C (crystal C) of an ulipristal acetate having an X-ray powder diffraction pattern comprising diffraction peaks at the following diffraction 2theta angles:
  • the diffraction angle having a peak includes a variable range of In the same crystalline form, even if a plurality of peak angles (including a variable range) formally overlaps with each other, each of the peak angles is independent in measurement.
  • the crystal C has diffraction peaks at and the angle of 9.1 to 9.2 o belongs to these two ranges. In this case, it means that there are two different independent peaks at different angles; one peak at
  • the ratio of the amorphous ulipristal acetate relative to the crystalline ulipristal acetate may be about 0.5/99.5 to 99.5/0.5 (e.g., about 10/90 to 99/1) in a weight ratio of the former/the latter.
  • the above-mentioned weight ratio can be determined based on the relationship between weight ratio and calorific value estimated by measuring the exothermic peak in a differential scanning calorimetry spectrum of a reference ulipristal acetate substance containing the amorphous ulipristal acetate and the crystalline ulipristal acetate in a predetermined weight ratio.
  • the instant invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the amorphous form or an ulipristal acetate substance according to the invention, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be used as a contraceptive, e.g., as an emergency contraceptive.
  • the pharmaceutical composition of the invention may be used for treating and/or preventing a gynecological disorder such as uterine fibroids, endometriosis, uterine bleedings, pain associated with dislocation of endometrium and the like.
  • An additional aspect of the invention is a method for producing an amorphous form or an ulipristal acetate substance of the invention.
  • the present invention further includes a process for producing an amorphous ulipristal acetate or an ulipristal acetate substance, which comprises dissolving a raw ulipristal acetate (e.g., a crystalline ulipristal acetate, such as a crystalline polymorphic form A) in a halogenated hydrocarbon and condensing the solution.
  • a raw ulipristal acetate e.g., a crystalline ulipristal acetate, such as a crystalline polymorphic form A
  • the present invention includes a process for producing an ulipristal acetate substance (or an ulipristal acetate mixture) containing an amorphous ulipristal acetate and a crystalline ulipristal acetate, which comprises pulverizing a raw ulipristal acetate (e.g., a crystalline ulipristal acetate, such as a crystalline polymorphic form A, B, or C).
  • a raw ulipristal acetate e.g., a crystalline ulipristal acetate, such as a crystalline polymorphic form A, B, or C.
  • an amorphous ulipristal acetate and an ulipristal acetate substance containing an amorphous ulipristal acetate have a higher solubility and more excellent absorption compared with a conventional crystalline form, and can improve bioavailability. Moreover, adding an amorphous ulipristal acetate to a crystalline ulipristal acetate allows the solubility of the crystalline ulipristal acetate to be improved.
  • the amorphous ulipristal acetate and the ulipristal acetate substance (or composition or mixture) according to the present invention are useful as an agent for preventing and/or treating uterine leiomyoma or other agents and also has an excellent safety as medicine (or pharmaceutical preparation).
  • the amorphous ulipristal acetate and the ulipristal acetate substance of the invention are useful as contraceptive.
  • Fig. 1 is a graph showing an X-ray powder diffraction spectrum of an amorphous ulipristal acetate of Example 1.
  • Fig. 2 is a graph showing a differential scanning calorimetry spectrum of the amorphous ulipristal acetate of Example 1.
  • Fig. 3 is a graph showing an X-ray powder diffraction spectrum of a crystal A of Comparative Example.
  • Fig. 4 is a graph showing a differential scanning calorimetry spectrum of the crystal A of Comparative Example.
  • Fig. 5 is a graph showing an X-ray powder diffraction spectrum of a crystal B of Example 3.
  • Fig. 6 is a graph showing a differential scanning calorimetry spectrum of the crystal B of Example 3.
  • Fig. 1 is a graph showing an X-ray powder diffraction spectrum of an amorphous ulipristal acetate of Example 1.
  • Fig. 3 is a graph showing an X-ray powder diffraction spectrum of
  • FIG. 7 is a graph showing an X-ray powder diffraction spectrum of a crystal C of Example 4.
  • Fig. 8 is a graph showing a differential scanning calorimetry spectrum of the crystal C of Example 4.
  • Fig. 9 is a graph showing a relationship between a pulverization time of the amorphous ulipristal acetate of Example 1 and an X-ray powder diffraction spectrum thereof.
  • Fig. 10 is a graph showing a relationship between a pulverization time of the crystal A of Comparative Example and an X-ray powder diffraction spectrum thereof.
  • an ulipristal acetate substance refers to ulipristal acetate in the form of a mixture or composition of polymorphic forms.
  • An ulipristal acetate substance according to the invention comprises at least amorphous form of ulipristal acetate of the invention.
  • the ulipristal acetate substance according to the invention comprises at least 5% by weight of the amorphous form of the invention, the weight percentage referring to the total weight of the ulipristal acetate substance.
  • the amorphous form encompasses at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% at least 80% at least 90% by weight of the amorphous form.
  • the amorphous form is the main polymorphic form of ulipristal acetate present within the ulipristal acetate substance of the invention. This means that the ulipristal acetate substance of the invention comprises no less than 50% by weight of amorphous form, preferably at least 90%, more preferably at least 95%, and even more preferably at least 99.5% by weight of amorphous form.
  • the remaining polymorphic forms present in the ulipristal acetate substance of the invention may be any crystalline forms of ulipristal acetate.
  • the ulipristal acetate substance of the invention essentially consists in amorphous form as described herein.
  • a feature of the present invention is an amorphous (amorphous-form or noncrystalline) ulipristal acetate.
  • the ulipristal acetate substance (or composition or mixture) of the present invention contains at least an amorphous (amorphous-form or noncrystalline) ulipristal acetate.
  • the amorphous ulipristal acetate or the ulipristal acetate substance is characterized by X-ray powder diffraction pattern. That is, the ulipristal acetate substance has at least a diffraction pattern derived from an amorphous ulipristal acetate in an X-ray powder diffraction spectrum.
  • the amorphous ulipristal acetate does not substantially have a diffraction peak derived from a crystal structure in an X-ray powder diffraction spectrum and has a halo pattern derived from scattering of an incident X-ray.
  • the amorphous ulipristal acetate of the invention has a X-ray diffraction pattern as depicted in Fig. 1.
  • the amorphous ulipristal acetate or the ulipristal acetate substance of the present invention is characterized by differential scanning calorimetry pattern. That is, the amorphous ulipristal acetate or the ulipristal acetate substance has at least a pattern derived from an amorphous ulipristal acetate in a differential scanning calorimetry spectrum.
  • the amorphous ulipristal acetate may show a downward shift of a baseline (a glass transition temperature (Tg)) at about 95 to 130 o C (e.g., about 100 to 125 o C, preferably about 105 to 120 o C) in a differential scanning calorimetry spectrum.
  • a baseline a glass transition temperature (Tg)
  • Tg glass transition temperature
  • the amorphous ulipristal acetate may have an exothermic peak at about 135 to 145 o C (e.g., about 137 to 143 o C, preferably about 139 to 141 o C) in the differential scanning calorimetry spectrum. It is presumed that the exothermic peak is a peak due to transition (or change) from amorphous form to crystalline form (form A).
  • the calorific value corresponding to the exothermic peak may be about 5 to 30 J, preferably about 8 to 28 J, more preferably 10 to 25 J (e.g., about 11 to 20 J) per gram of the amorphous ulipristal acetate.
  • the above-mentioned calorific value can be calculated based on the weight and exothermic peak area of an amorphous ulipristal acetate to be subjected to a differential scanning calorimeter (DSC).
  • DSC differential scanning calorimeter
  • the amorphous ulipristal acetate may have an endothermic peak at about 180 to 192 o C, preferably about 183 to 190 o C in the differential scanning calorimetry spectrum. It is presumed that the endothermic peak is a peak due to melting of the transition crystal (crystal A).
  • the amorphous ulipristal acetate of the invention has differential scanning calorimetry spectrum as depicted in Fig. 2.
  • the ulipristal acetate substance of the invention contains the amorphous ulipristal acetate.
  • the ulipristal acetate substance of the invention may further contain a crystalline ulipristal acetate (polymorphic crystal of ulipristal acetate).
  • Examples of the crystalline ulipristal acetate may include the following: (1) a crystalline polymorphic form A (crystal A) of an ulipristal acetate having an X-ray powder diffraction spectrum comprising diffraction peaks at the following diffraction angle 2theta: (2) a crystalline polymorphic form B (crystal B) of an ulipristal acetate having an X-ray powder diffraction spectrum comprising diffraction peaks at the following diffraction angle 2theta: and (3) a crystalline polymorphic form C (crystal C) of an ulipristal acetate having an X-ray powder diffraction spectrum comprising diffraction peaks at the following diffraction angle 2theta:
  • the X-ray powder diffraction spectrum can be measured according to a common method, preferably using a diffractometer with Cu K alpha-1 radiation source, for example, the condition of Examples mentioned below.
  • the diffraction angle 2theta of the diffraction peak sometimes varies within a range of about depending on the measurement conditions and the state of samples.
  • the same crystal structure has almost the same X-ray powder diffraction pattern without significant change in the number of characteristic diffraction peaks.
  • a crystalline polymorphic form A having an endothermic peak (melting point) at about 180 to 192 o C (preferably about 183 to 190 o C) in the differential scanning calorimetry spectrum
  • a crystalline polymorphic form B having an endothermic peak (melting point) at about 160 to 170 o C (e.g., about 165 to 169 o C, preferably about 166 to 168 o C) in the differential scanning calorimetry spectrum
  • a crystalline polymorphic form C having an endothermic peak (melting point) at about 135 to 145 o C (e.g., about 137 to 143 o C, preferably about 139 to 141 o C) in the differential scanning calorimetry spectrum, and others.
  • the crystalline polymorphic form C may further have an exothermic peak at about 145 to 170 o C (e.g., about 160 to 167 o C, preferably about 163 to 165 o C) in the differential scanning calorimetry spectrum or may further have an endothermic peak at about 180 to 192 o C (preferably about 183 to 190 o C). It is presumed that the exothermic peak is a peak due to transition to the crystalline polymorphic form A (crystal A) from the crystalline polymorphic form C (crystal C). It is presumed that the endothermic peak is a peak due to melting of the crystalline polymorphic form A (crystal A).
  • the crystalline form A may have the X-ray powder diffraction pattern as depicted in Fig. 3 or described in Table 1 and/or the differential scanning calorimetry spectrum as shown in Fig. 4.
  • the crystalline form B may have the X-ray powder diffraction pattern as shown in Fig. 5 or described in Table 2 and/or the differential scanning calorimetry spectrum as shown in Fig. 6.
  • the crystalline form C may have the X-ray powder diffraction pattern as shown in Fig. 7 or described in Table 3 and/or the differential scanning calorimetry spectrum as shown in Fig. 8.
  • the crystalline ulipristal acetates may be used alone or in combination.
  • the crystal B and the crystal C are preferred in terms of solubility.
  • the crystalline ulipristal acetate (or each crystalline polymorphic form) may be a single crystal or may be a twin crystal or a polycrystal.
  • the form (external form) of the crystalline ulipristal acetate (or each crystalline polymorphic form) is not particularly limited to a specific one.
  • the form of the crystalline ulipristal acetate may be triclinic, monoclinic, rhombic (orthorhombic), tetragonal, cubic, trigonal (rhombohedral), hexagonal, or other forms.
  • the crystalline ulipristal acetate may be a spherulite, a skeleton crystal, a dendrite, a needle crystal (for example, a crystal whisker), or others.
  • the ratio (weight ratio) of the amorphous ulipristal acetate relative to the crystalline ulipristal acetate can be selected from the range of about 0.5/99.5 to 99.5/0.5 (e.g., about 1/99 to 99/1) in a ratio of the former/the latter.
  • the ratio may be about 10/90 to 99/1 (e.g., about 20/80 to 99/1), preferably about 30/70 to 98/2 (e.g., about 40/60 to 97/3), and more preferably about 50/50 to 96/4 (e.g., about 60/40 to 95/5, preferably about 70/30 to 95/5).
  • the above ratio may be about 15/85 to 85/15 (e.g., about 25/75 to 75/25), preferably about 30/70 to 70/30 (e.g., about 40/60 to 60/40) in a ratio of the former/the latter.
  • the ulipristal acetate substance (ulipristal acetate mixture, composition or mixed crystal) containing the amorphous ulipristal acetate and the crystalline ulipristal acetate has structural characteristics derived from these respective forms (e.g., a diffraction peak in an X-ray powder diffraction spectrum, an endothermic peak in a differential scanning calorimetry spectrum).
  • a diffraction peak in an X-ray powder diffraction spectrum an endothermic peak in a differential scanning calorimetry spectrum
  • the intensity ratio of the diffraction peaks (or the endothermic peaks) of these respective forms often corresponds to the mixing ratio of these respective forms.
  • the ulipristal acetate (the ulipristal acetate substance, mixture, composition or mixed crystal, or the amorphous ulipristal acetate or each polymorphic crystalline ulipristal acetate) may further contain a low molecular weight compound (or a solvent) [or a low molecular weight compound (or a solvent) may adhere to the ulipristal acetate].
  • the low molecular weight compound (or the solvent) is not particularly limited to a specific one as far as the low molecular weight compound (or the solvent) is pharmaceutically acceptable.
  • the low molecular weight compound may include water and an organic solvent [for example, a halogenated hydrocarbon (e.g., chloroform), an alcohol (e.g., a C 1-4 alkanol such as 1-propanol or 2-propanol), an ether (e.g., a cyclic ether such as tetrahydrofuran), a ketone (e.g., acetone), an ester (e.g., ethyl formate), a sulfoxide (e.g., dimethylsulfoxide), an amide (e.g., N,N-dimethylformamide), and a cyclic amine (e.g., pyridine)].
  • a halogenated hydrocarbon e.g., chloroform
  • an alcohol e.g., a C 1-4 alkanol such as 1-propanol or 2-propanol
  • an ether e.g., a cyclic ether such
  • low molecular weight compounds or solvents may be used alone or in combination.
  • the amount of the low molecular weight compound (or the adhering amount thereof) relative to 100 parts by weight of the ulipristal acetate may for example be about not more than 30 parts by weight, preferably about not more than 20 parts by weight, and more preferably about not more than 10 parts by weight (e.g., about 0.001 to 1 parts by weight).
  • the particle size of the amorphous ulipristal acetate or the ulipristal acetate substance is not particularly limited to a specific one.
  • the average particle size (average particle diameter) of the amorphous ulipristal acetate or the ulipristal acetate substance based on a laser diffraction may be about 0.1 micrometers to 1 millimeter (e.g., about 0.5 micrometers to 1 millimeter) and preferably about 1 to 500 micrometers (e.g., about 2 to 100 micrometers) or is usually about 5 to 50 micrometers (e.g., about 5 to 30 micrometers).
  • the average particle size of the ulipristal acetate may be about 0.1 to 5 micrometers (e.g., about 0.5 to 3 micrometers).
  • the amorphous ulipristal acetate or the ulipristal acetate substance of the invention may be micronized.
  • the amorphous ulipristal acetate and the ulipristal acetate substance are highly soluble in a solvent and have an excellent bioavailability.
  • the process for producing the ulipristal acetate substance or the amorphous ulipristal acetate of the invention is not particularly limited to a specific one as far as the above-mentioned X-ray powder diffraction spectrum or differential scanning calorimetry spectrum is obtained.
  • the process for producing the ulipristal acetate substance or the amorphous ulipristal acetate of the invention comprises, for example, (i) a step for dissolving a raw ulipristal acetate (e.g., a crystalline ulipristal acetate) in a halogenated hydrocarbon and condensing the solution.
  • a raw ulipristal acetate e.g., a crystalline ulipristal acetate
  • the raw ulipristal acetate can be produced by a common method.
  • the raw ulipristal acetate can be prepared by allowing 3,3-(1,2-ethanedioxy)-5alpha-hydroxy-11beta-(4-N,N-dimethylaminophenyl)-17alpha-acetoxy-19-norpregna-9-ene-20-one to react with an acid (for example, an organic acid such as acetic acid or trifluoroacetic acid; and an inorganic acid such as hydrochloric acid, sulfuric acid, monopotassium sulfate, or phosphoric acid).
  • an acid for example, an organic acid such as acetic acid or trifluoroacetic acid; and an inorganic acid such as hydrochloric acid, sulfuric acid, monopotassium sulfate, or phosphoric acid.
  • the details of the reaction may for example be referred to Japanese Patent Application Laid-Open Publication Nos. 2006-519255, 2006-515869,
  • the above-mentioned reaction mixture may be used as it is, or a crude purified product obtained by purifying the reaction mixture with a common purification means (such as filtration, centrifugation, or chromatography) may be used.
  • a common purification means such as filtration, centrifugation, or chromatography
  • the raw ulipristal acetate there may be used a crystalline ulipristal acetate obtained by crystallization (or recrystallization) from a solution (a crystallization system) containing the above-mentioned reaction mixture (or crude purified product) and a crystallization solvent.
  • a crystalline ulipristal acetate obtained by repeating the crystallization step a plurality of times (for example, twice to four times).
  • the halogen atom of the halogenated hydrocarbon may include chlorine, bromine, and others.
  • the preferred halogen atom includes chlorine.
  • As the halogenated hydrocarbon there may be exemplified a haloC 1-2 alkane, for example, dichloromethane, 1,2-dichloroethane, chloroform, trichloroethylene, carbon tetrachloride, a combination thereof, and others.
  • a dichloroC 1-2 alkane such as dichloromethane is preferred.
  • the ratio of the halogenated hydrocarbon relative to 1 g of the raw ulipristal acetate may for example be about 0.1 to 50 mL, preferably about 0.5 to 40 mL, and more preferably about 1 to 30 mL (e.g., about 5 to 20 mL).
  • the condensation may be carried out under a room temperature to a heated temperature (for example, at a temperature of about 20 to 100 o C, preferably about 25 to 95 o C, and more preferably about 30 to 90 o C). Moreover, the condensation may be carried out under a reduced pressure to an atmospheric pressure (for example, at a pressure of about 50 to 1013 hPa, preferably about 70 to 1000 hPa, more preferably about 100 to 900 hPa, usually not more than 500 hPa). Further, the condensation rate may for example be about 0.01 to 10 mL/minute, preferably about 0.1 to 8 mL/minute, and more preferably about 1 to 5 mL/minute.
  • the condensed product may be dried (such as by air drying, through circulation drying, or drying under a reduced pressure).
  • the condensed product is usually dried under a reduced pressure [for example, dried under not more than 50 hPa, preferably not more than 20 hPa (e.g., about 1 to 15 hPa)].
  • the drying may be carried out under a room temperature to a heated temperature, preferably about 25 to 80 o C, and more preferably about 30 to 70 o C (e.g., about 40 to 70 o C).
  • the drying time may for example be about 1 to 20 hours (e.g., about 5 to 20 hours) and preferably about 1.5 to 18 hours (e.g., about 10 to 18 hours).
  • the amorphous ulipristal acetate can be produced efficiently by condensation and drying in such a manner, in particular, by condensation and drying of a solution of a raw ulipristal acetate in a halogenated hydrocarbon under a reduced pressure with heating.
  • the step (i) may be conducted repeatedly a plurality of times (for example twice to four times).
  • the production process of the ulipristal acetate substance may comprise, in addition to the step (i), a step (ii) forming a crystalline ulipristal acetate by crystallization or transition (transformation) in association with the solvent (crystallization from the solution, condensation of the solution, transition in the solution or dispersion medium) and a step (iii) for mixing the amorphous ulipristal acetate obtained in the step (i) and the crystalline ulipristal acetate obtained in the step (ii).
  • the method for forming the crystalline ulipristal acetate is not particularly limited to a specific one.
  • the method may include a cooling method (a method which comprises dissolving a raw ulipristal acetate in a solvent and cooling the solution), a poor-solvent addition method (a method which comprises dissolving a raw ulipristal acetate in a solvent and adding a poor solvent to the solution), an evaporation method (a method which comprises dissolving a raw ulipristal acetate in a solvent and condensing the solution), and a stir-suspension method (a method which comprises dispersing a raw ulipristal acetate in a solvent and stirring the dispersion).
  • a cooling method a method which comprises dissolving a raw ulipristal acetate in a solvent and cooling the solution
  • a poor-solvent addition method a method which comprises dissolving a raw ulipristal acetate in a solvent and adding a poor solvent
  • the raw ulipristal acetate to be subjected to the step for forming the crystalline ulipristal acetate may include, for example, the raw ulipristal acetate described in the item of the step (i).
  • the solvent may include water, an organic solvent [for example, an aliphatic hydrocarbon (e.g., hexane), an aromatic hydrocarbon (e.g., toluene), an alcohol (e.g., an C 1-4 alkanol such as ethanol, 1-propanol, 2-propanol, or 1-butanol), an ester (e.g., ethyl formate, ethyl acetate, isopropyl acetate, and isobutyl acetate), a ketone (e.g., acetone and methyl ethyl ketone), an ether (e.g., an acyclic ether such as diethyl ether; and a cyclic ether such as dioxane or tetrahydrofuran), a sulfoxide (e.g., dimethylsulfoxide), an amide (e.g., N,N-dimethylformamide and
  • the ratio of the solvent relative to 1 g of the raw ulipristal acetate may for example be about 0.1 to 500 mL, preferably about 0.5 to 400 mL, and more preferably about 1 to 300 mL (e.g., about 2 to 200 mL).
  • the crystal A may for example be prepared by dissolving an isopropanol-solvated crystal of ulipristal acetate in a mixed solvent containing ethanol and water and adding a seed crystal (crystalline polymorphic form A or B) to the solution for crystallization.
  • the crystal B may for example be prepared by dissolving the raw ulipristal acetate in ethanol and cooling (rapidly cooling) the solution, or may be prepared by dissolving the raw ulipristal acetate in at least one solvent selected from the group consisting of ethanol, 1-propanol, and ethyl acetate and condensing the solution.
  • the crystal C may for example be prepared by dissolving an isopropanol-solvated crystal of ulipristal acetate in a mixed solvent containing ethanol and water and crystallizing the solution without addition of a seed crystal to the solution.
  • the ratio (volume ratio) of ethanol relative to water may for example be about 85/15 to 75/25 in a ratio of the former/the latter.
  • the method for mixing the amorphous ulipristal acetate and the crystalline ulipristal acetate is not particularly limited to a specific one.
  • the amorphous ulipristal acetate and the crystalline ulipristal acetate are usually mixed by a common mixer [for example, a vessel-rotary mixer (such as a rotary drum type, double corn type, or V-shape type) and a stationary mixer (such as a ribbon type or a screw type)] in practical cases.
  • a common mixer for example, a vessel-rotary mixer (such as a rotary drum type, double corn type, or V-shape type) and a stationary mixer (such as a ribbon type or a screw type)
  • the mixing ratio of the amorphous ulipristal acetate relative to the crystalline ulipristal acetate can suitably be selected depending on respective contents.
  • the ulipristal acetate substance containing the amorphous ulipristal acetate and the crystalline ulipristal acetate may be prepared through the steps (i) to (iii) or, in terms of productivity, may be prepared through (iv) a step for pulverizing (or finely pulverizing) a raw ulipristal acetate (e.g., a crystalline ulipristal acetate, such as a crystal A, a crystal B, or a crystal C) without passing through the steps (i) to (iii).
  • a raw ulipristal acetate e.g., a crystalline ulipristal acetate, such as a crystal A, a crystal B, or a crystal C
  • the method for pulverizing the raw ulipristal acetate can suitably be selected depending on a desired grain size (or particle size) and a proportion of the noncrystalline.
  • the method may be a method which comprises pulverizing the raw ulipristal acetate in a mortar or a method which comprises pulverizing the raw ulipristal acetate using a compression or impact crusher (such as a crusher, an atomizer, or a hammer mill); a shear crusher (such as a cutter mill); a hammering crusher (such as a ball mill); an attrition crusher (such as a roller mill); or others.
  • a compression or impact crusher such as a crusher, an atomizer, or a hammer mill
  • a shear crusher such as a cutter mill
  • a hammering crusher such as a ball mill
  • an attrition crusher such as a roller mill
  • the present invention is suitable for producing a preparation through a pulverization step or a compression step (or a tableting step).
  • the amorphous ulipristal acetate or ulipristal acetate substance of the present invention has not only an antiprogestational activity but also an antiglucocorticoidal activity, the amorphous ulipristal acetate or ulipristal acetate substance is preferably used as a selective progesterone receptor modulator.
  • the amorphous ulipristal acetate or ulipristal acetate substance of the present invention is useful for preventing and/or treating of a gynecological disease [for example, uterine leiomyoma or a disease attributable to uterine leiomyoma (e.g., metastatic leiomyoma, dysmenorrhea, menorrhagia, anemia, infertility, constipation, pollakiuria, and lumbago)].
  • a gynecological disease for example, uterine leiomyoma or a disease attributable to uterine leiomyoma (e.g., metastatic leiomyoma, dysmenorrhea, menorrhagia, anemia, infertility, constipation, pollakiuria, and lumbago)].
  • a gynecological disease for example, uterine leiomyoma or a disease attribu
  • amorphous ulipristal acetate or the ulipristal acetate substance of the invention may be also useful as a drug, for instance for treating and/or preventing a gynecological disorder.
  • gynecological disorders encompass, without being limited to, uterine fibroids or leiomyoma, endometriosis, uterine bleedings, pain associated with dislocation of endometrium and the like.
  • the invention also relates to a method for treating a female patient preferably suffering from a gynecological disorder comprising administering a therapeutic effective amount of the amorphous ulipristal acetate or that of the ulipristal acetate substance of the invention to said patient.
  • a further aspect of the invention is a method for providing contraception to a woman in need thereof, comprising administering said woman with a contraceptive amount of the amorphous ulipristal acetate or the ulipristal acetate substance of the invention.
  • the contraceptive method of the invention may be an emergency contraceptive method wherein the administration of the amorphous ulipristal acetate or that of the ulipristal acetate substance of the invention occurs within 120 hours after an unprotected intercourse.
  • the contraceptive method may be a regular contraceptive method wherein the administration of ulipristal acetate is repeated several days in a row within the menstrual cycle.
  • the contraceptive method of the invention may be an on-demand contraception method as described in WO2010/119029, the disclosure of which being incorporated by reference.
  • the administration of ulipristal acetate in contraceptive methods of the invention is oral.
  • the invention also relates to the use of the amorphous ulipristal acetate or that of an ulipristal acetate substance of the invention in the manufacture of a contraceptive or in the manufacture of a drug for treating a gynecological disorder.
  • the above-mentioned amorphous ulipristal acetate or the ulipristal acetate substance may be used as a medicine alone, or the above-mentioned amorphous ulipristal acetate or the ulipristal acetate substance may be used in combination with a carrier (e.g., a pharmacologically or physiologically acceptable carrier) to provide a pharmaceutical composition (or a preparation).
  • a carrier e.g., a pharmacologically or physiologically acceptable carrier
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the amorphous ulipristal acetate or the ulipristal acetate substance of the invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition of the invention is such that at least 5% by total weight of the ulipristal acetate present in the pharmaceutical composition is the amorphous ulipristal acetate of the invention.
  • ulipristal acetate present within the composition is mainly amorphous. This means that the pharmaceutical composition of the invention may comprise no less 50% of amorphous ulipristal acetate of the invention with respect to total weight of ulipristal acetate present within the composition.
  • the amorphous ulipristal acetate of the invention accounts for at least 60%, preferably at least 80% and even at least 90% by weight with respect to the total weight of ulipristal acetate present within the composition.
  • the pharmaceutical composition may comprise from 0.01% to 80% by weight of the amorphous ulipristal acetate or the ulipristal acetate substance of the invention and from 20% to 99.99% by weight of excipient(s).
  • the excipient(s) may be suitably selected depending on the form of the composition or preparation (that is, the dosage form), the route of administration, the application (or use), and others.
  • the dosage form is not particularly limited to a specific one and may be a solid preparation (for example, powdered preparations, powders, granulated preparations (e.g., granules and microfine granules or the like), spherical or spheroidal preparations, pills, tablets, capsules (including soft capsules and hard capsules), dry syrups, and suppositories), a semisolid preparation (for example, creams, ointments, gels, gumdrop-like preparations, and film-like preparations, sheet-like preparations), a liquid preparation (for example, solutions, suspensions, emulsions, syrup, elixir, lotions, injectable solutions (or injections), and drops), and others.
  • a solid preparation for example, powdered preparations, powders, granul
  • the capsules may be a capsule filled with a liquid or a capsule filled with a solid preparation (such as granules).
  • the preparation may be a lyophilized preparation.
  • the preparation of the present invention may be a preparation releasing the active ingredient(s) at a controlled rate (a sustained release preparation or a rapid-release preparation).
  • the preparation may be an oral dosage form [for example, granules, powders, tablets (e.g., sublingual tablets and orally disintegrating tablets), capsules, syrup, emulsions, suspensions, jellys, gumdrop-like preparations, and film preparations] or a parenteral dosage form (for example, inhalants, preparations for transdermal administration, and preparations for transnasal administration).
  • the preparation may be topical or local administration form [for example, injections (e.g., hypodermic injections, intravenous injections, intramuscular injections, and intraabdominal injections), suspensions, ointments, plasters and pressure sensitive adhesives, cataplasms.
  • the excipient(s) may suitably be selected, for example, depending on the administration route and the application of preparation, from components (e.g., an excipient, a binder, a disintegrant, a lubricant, and a coating agent) listed in Japanese Pharmacopoeia, (1) Handbook of Pharmaceutical Excipients (Maruzen Company, ltd., (1989)), (2) Japanese Pharmaceutical Excipients Dictionary 2007 (Yakuji Nippo Ltd., issued July, 2007), (3) Pharmaceutics, revised fifth edition (Nankodo, Co., Ltd. (1997)), and (4) Japanese Pharmaceutical Excipients 2003 (Yakuji Nippo Ltd., issued August, 2003).
  • the excipient for a solid preparation is practically at least one member selected from the group consisting of a diluent, a binder, and a disintegrant.
  • the pharmaceutical composition may contain a lipid.
  • the diluent may include a saccharide or a sugar alcohol such as lactose, glucose, sucrose, mannitol, sorbitol, or xylitol; a starch such as a corn starch; a polysaccharide such as a crystalline cellulose (including a microcrystalline cellulose); silicon dioxide or a silicate such as a light silicic anhydride; and others.
  • a saccharide or a sugar alcohol such as lactose, glucose, sucrose, mannitol, sorbitol, or xylitol
  • a starch such as a corn starch
  • a polysaccharide such as a crystalline cellulose (including a microcrystalline cellulose)
  • silicon dioxide or a silicate such as a light silicic anhydride
  • the binder may include a soluble starch such as a pregelatinized starch or a partially pregelatinized starch; a polysaccharide such as gum acacia (or gum arabic), dextrin, or sodium alginate; a synthetic polymer such as a polyvinylpyrrolidone (PVP), a polyvinyl alcohol (PVA), a carboxyvinyl polymer, a polyacrylic polymer, a polylactic acid, or a polyethylene glycol; a cellulose ether such as a methyl cellulose (MC), an ethyl cellulose (EC), a carboxymethyl cellulose (CMC), a carboxymethyl cellulose sodium, a hydroxyethyl cellulose (HEC), a hydroxypropyl cellulose (HPC), or a hydroxypropylmethyl cellulose (HPMC); and others.
  • a soluble starch such as a pregelatinized starch or a partially pregelatinized starch
  • the disintegrant may include a sodium carboxymethyl starch, a carmellose, a carmellose sodium, a carmellose calcium, a croscarmellose sodium, a crospovidone, a low-substituted hydroxypropyl cellulose, and others. These excipients may be used alone or in combination.
  • the pharmaceutical composition may be a coated form.
  • a saccharide or a sugar a cellulose derivative such as an ethyl cellulose or a hydroxymethyl cellulose, a poly(oxyethylene glycol), a cellulose acetate phthalate, a hydroxypropylmethyl cellulose phthalate, a methyl methacrylate-(meth)acrylic acid copolymer, and eudragit (a copolymer of methacrylic acid and acrylic acid).
  • a saccharide or a sugar a cellulose derivative such as an ethyl cellulose or a hydroxymethyl cellulose, a poly(oxyethylene glycol), a cellulose acetate phthalate, a hydroxypropylmethyl cellulose phthalate, a methyl methacrylate-(meth)acrylic acid copolymer, and eudragit (a copolymer of methacrylic acid and acrylic acid).
  • the coating agent may be an enteric component (e.g., a cellulose phthalate, a hydroxypropylmethyl cellulose phthalate, and a methyl methacrylate-(meth)acrylic acid copolymer) or a gastric soluble component comprising a polymer (e.g., eudragit) containing a basic component such as a dialkylaminoalkyl(meth)acrylate.
  • the preparation may be a capsule having such an enteric component or gastric soluble component as a capsule shell.
  • the pharmaceutical composition may be a coated or uncoated tablet.
  • additives can be suitably used depending on an administration route, a dosage form, and others.
  • Such an additive may include, for example, a lubricant, a disintegrant aid, an antioxidation agent or an antioxidant, an emulsifier, a dispersing agent, a suspending agent, a dissolving agent, a dissolution aid, a thickener, a pH adjusting agent or a buffer, a stabilizer, an antiseptic agent or a preservative, a fungicide or antibacterial agent, an antistatic agent, a corrigent or a masking agent, a coloring agent, a deodorant or a perfume, an algefacient, an antifoaming agent, an isotonizing agent, and a soothing agent.
  • a lubricant e.g., a lubricant, a disintegrant aid, an antioxidation agent or an antioxidant, an emulsifier, a dispersing agent, a suspending agent, a dissolv
  • the pharmaceutical composition (or pharmaceutical preparation) of the present invention may contain other physiologically active components or pharmacologically active components (for example, a follicle hormone (or an estrogen preparation)) if necessary.
  • physiologically active components for example, a follicle hormone (or an estrogen preparation)
  • pharmacologically active components for example, a follicle hormone (or an estrogen preparation)
  • the pharmaceutical composition of the present invention may be prepared by using an excipient component in addition to an effective ingredient, and if necessary, an additive and the like, with a conventional preparation manner (for example, a production process described in Japanese Pharmacopoeia 16 th edition or a process in accordance with the production process).
  • the pharmaceutical composition may comprise from 1 mg to 50 mg, preferably from 5 mg to 40 mg of ulipristal acetate per dosage unit, for instance 5, 10, 15, 20 or 30 mg per dosage unit.
  • the amorphous ulipristal acetate or the ulipristal acetate substance of the present invention (also including the agent for preventing and/or treating a gynecological disease, the contraceptive, and the pharmaceutical composition), which has a low toxicity and an excellent safety, is safely administered to female human beings and non-humans, usually mammals (for example, human beings, mice, rats, rabbits, dogs, cats, bovines, horses, pigs, and monkeys).
  • the amount to be administered (or dose) may be selected according to the species, age, body weight, and condition (e.g., a performance status, a condition of a disease, a presence of a complication) of the subject to be administered, the duration (or period or schedule) of administration, the dosage form, the method (or route) of administration, and others.
  • the amount to be administered (or dose) to human beings is about 1 to 50 mg/day and preferably about 5 to 40 mg/day.
  • the method (or route) of administration may be an oral administration or a local or parenteral administration (for example, hypodermic administration, intravenous administration, intramuscular administration, transrectal administration, and transvaginal administration).
  • a local or parenteral administration for example, hypodermic administration, intravenous administration, intramuscular administration, transrectal administration, and transvaginal administration.
  • the frequency of administration is not particularly limited to a specific one.
  • the frequency of administration may be once a day or if necessary may be a plurality times a day (e.g., twice to three times a day).
  • X-ray powder diffraction spectrum The X-ray powder diffraction (XRD) spectrum was measured under the following conditions: radiation source: Cu K(alpha1), tube voltage: 40 kV, tube current: 40 mA, sampling interval: 0.1 o , scanning speed: 10 o /minute. In the X-ray powder diffraction chart, the diffraction peak was searched by second order differential as a peak width threshold of 0.1 o .
  • differential scanning calorimetry spectrum The differential scanning calorimetry spectrum was measured using a differential scanning calorimeter (type: DSC8230L) at a rate of heating of 2 o C/minute.
  • the solid of the separated portion was filtered out, and the ulipristal acetate content of the residue was quantitatively determined using a high-performance liquid chromatography (column: ODS, column temperature: 40 o C, eluate: 0.1% trifluoroacetic acid aqueous solution/acetonitrile mixture (volume ratio 3:2), rate of flow: 1.0 mL/minute, detection: UV 302 nm), and the solubility was calculated.
  • the absorption test was performed as follows.
  • the ulipristal acetate was filled into a gelatin capsule shell (manufacturer: Qualicaps Co., Ltd., size: No. 00, lot: C0079A) to produce a capsule.
  • the capsule was orally administered to 6 female dogs at a dose of 25 mg/kg (in terms of ulipristal acetate).
  • the blood was collected 0.5, 1, 2, 4, 6, 24, and 48 hours after the oral administration. Then the sample was centrifuged to give a plasma.
  • the concentration of the ulipristal acetate in the plasma was measured by a LC-MS/MS (liquid chromatography - tandem mass spectrometry) method, and the elimination half-life (T 1/2 ), the time to the maximum plasma concentration (T max ), and the maximum plasma concentration (C max ) were calculated.
  • the capsule was administered to each female dog twice at dosing intervals (washout period) of one week by crossover method.
  • the form retention after pulverization was calculated based on the peak intensity ratio in XRD.
  • corrections of the measurements was made by using a peak intensity of a silicon standard substance for inspection at every measurement date.
  • the resulting organic phase was vacuum-concentrated to give a raw ulipristal acetate residue.
  • To the residue was added 38.5 mL of isopropanol, and the mixture was vacuum-concentrated.
  • To the resulting residue was added the same amount (38.5 mL) of isopropanol, the mixture was vacuum-concentrated again.
  • To the resulting solid product were added 77 mL of isopropanol, and the mixture was heated for dissolution. The solution was allowed to cool to 0 to 5 o C, and the temperature was maintained for one hour.
  • the obtained suspension was filtered and the cake was washed with cold isopropanol to give an isopropanol hemisolvate crystal at a yield of 96% by mol.
  • an ulipristal acetate was crystallized in accordance with Japanese Patent Application Laid-Open Publication No. 2006-515869 (JP-2006-515869A) to give 7.5 g of a crystalline polymorphic form A of ulipristal acetate (crystal A), which had a melting point of 189 o C.
  • Example 1 The ulipristal acetate crystal (1.5 g) obtained in Comparative Example was dissolved in 10 mL of dichloromethane, and the solution was vacuum-concentrated in a 60 o C water bath at a pressure of not more than 500 hPa for 2 to 3 minutes. The resulting residue was dried at a temperature of 50 o C under a reduced pressure of not more than 15 hPa for 15 hours to give 1.5 g of an amorphous ulipristal acetate.
  • the X-ray powder diffraction spectrum of the amorphous form is shown in Fig. 1, and the differential scanning calorimetry spectrum thereof is shown in Fig. 2.
  • Example 2 The ulipristal acetate crystal (0.1 g) obtained in Comparative Example and the amorphous form (0.1 g) obtained in Example 1 were mixed to give an ulipristal acetate (crystal A).
  • the X-ray powder diffraction spectrum of the crystal A is shown in Fig. 3, and the differential scanning calorimetry spectrum thereof is shown in Fig. 4.
  • the diffraction peak intensity and relative intensity in each diffraction angle (grid interval d value) of the crystal A are shown in Table 1.
  • Example 3 The ulipristal acetate crystal (1.3 g) obtained in Comparative Example was dissolved in 6.5 mL of ethanol by heating. The solution was allowed to stand at 26 o C for one hour and then at 4 o C for 16 hours. The resulting precipitate was separated by filtration and dried under a reduced pressure until the weight reached a constant value, and 1.0 g of a crystal B was obtained. The crystal B (0.1 g) and the amorphous form (0.1 g) obtained in Example 1 were mixed to give an ulipristal acetate (crystal B).
  • the X-ray powder diffraction spectrum of the crystal B is shown in Fig. 5, and the differential scanning calorimetry spectrum thereof is shown in Fig. 6. Moreover, the diffraction peak intensity and relative intensity in each diffraction angle (grid interval d value) of the crystal B are shown in Table 2.
  • Example 4 The ulipristal acetate crystal (1.761 g) obtained in Comparative Example was dissolved in 10 mL of isopropanol by heating, and the solvent was distilled off under a reduced pressure. The resulting residue was dissolved in 9 mL of isopropanol by heating, and the solvent was distilled off under a reduced pressure. The resulting residue was dissolved in 9 mL of isopropanol by heating, and the solution was allowed to stand in ice-water bath for one hour. The precipitate was separated by filtration to give an ulipristal acetate isopropanol hemisolvate wet crystal (1.782 g).
  • the resulting precipitate was separated by filtration and dried at 100 o C under a reduced pressure to give 1.0 g of a crystal C.
  • the crystal C (0.1 g) and the amorphous form (0.1 g) obtained in Example 1 were mixed to give an ulipristal acetate substance.
  • the X-ray powder diffraction spectrum of the crystal C is shown in Fig. 7, and the differential scanning calorimetry spectrum thereof is shown in Fig. 8.
  • the diffraction peak intensity and relative intensity in each diffraction angle (grid interval d value) of the crystal C are shown in Table 3.
  • Examples 1 to 4 show significantly high solubility and excellent bioavailability compared with Comparative Example.
  • Example 1 is excellent in the respects of all of T max , and C max compared with Comparative Example and shows excellent pharmacokinetics as a pharmaceutical product which is quickly be absorbed into the body.
  • Example 1 A capsule was obtained by filling the amorphous form obtained in Example 1 into a capsule shell (Size 0).
  • Example 2 The amorphous form obtained in Example 1 and carrier components were mixed in accordance with the following formulation. The mixture was granulated by dry granulating and then sized to give a granule.
  • Preparation Example 3 The granule obtained in Preparation Example 2 and carrier components were mixed in accordance with the following formulation. The mixture was subjected to tablet compression to give a tablet.
  • Preparation Example 4 The tablet obtained in Preparation Example 3 was coated with a coating agent having the following formulation to give a film-coated tablet.
  • the amorphous ulipristal acetate or the ulipristal acetate substance of the present invention has an extremely high solubility and more excellent absorption compared with a conventional crystalline form, and can improve bioavailability. Therefore, the amorphous ulipristal acetate or the ulipristal acetate substance of the present invention is preferably used as a selective progesterone receptor modulator.
  • the amorphous ulipristal acetate or the ulipristal acetate substance of the present invention is useful for prevention and/or treatment of a gynecological disease [for example, uterine leiomyoma or a disease attributable to uterine leiomyoma (e.g., metastatic leiomyoma, dysmenorrhea, menorrhagia, anemia, infertility, constipation, pollakiuria, and lumbago)].
  • a gynecological disease for example, uterine leiomyoma or a disease attributable to uterine leiomyoma (e.g., metastatic leiomyoma, dysmenorrhea, menorrhagia, anemia, infertility, constipation, pollakiuria, and lumbago)].
  • a gynecological disease for example, uterine leiomyoma or a disease attribu

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EP2900683B1 (fr) * 2012-09-28 2018-03-14 ASKA Pharmaceutical Co., Ltd. Forme polymorphe cristalline d'acétate d'ulipristal

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